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Lifestyle Therapy Targeting Hyperinsulinemia Normalizes Hyperglycemia and Surrogate Markers of Insulin Resistance in a Large, Free-Living Population

Open AccessPublished:September 15, 2022DOI:https://doi.org/10.1016/j.focus.2022.100034

      Highlights

      • Targeting hyperinsulinemia improves all surrogate markers of insulin resistance.
      • Effective lifestyle treatment can be delivered by a team of low-cost health workers.
      • Lifestyle modification is effective at reducing Metabolic Syndrome Severity Scores.
      • Improvement in metabolic syndrome and hyperglycemia was sustained for nearly 2 years.
      • Team-based lifestyle intervention may reduce the disease burden of diabetes and coronary heart disease.

      Introduction

      This article reports the evaluation of a personalized, team-based comprehensive lifestyle modification program targeting known triggers of hyperinsulinemia and insulin resistance.

      Methods

      A retrospective chart review was undertaken for 536 participants in a novel high-intensity lifestyle behavioral modification program. Surrogate markers of insulin resistance and metabolic syndrome‒related pathologies were measured before and after participation in the the program.

      Results

      Reversal of metabolic syndrome was present in 42% of participants who met the criteria for this syndrome. Additional changes seen in this cohort include: 36% decrease in triglyceride to high-density lipoprotein cholesterol ratio; 5% (–7.2 mm Hg) decrease in systolic blood pressure and 4% (–3.8 mm Hg) decrease in diastolic blood pressure; decreased abdominal adiposity and waist circumference (–7.6 cm); increased high-density lipoprotein cholesterol (1.3 mg/dL); and 23% (–57.1 mg/dL) decrease in serum triglycerides. Hyperglycemia was normalized in 35% of participants with prediabetes. Only 2% of those with prediabetes progressed to type 2 diabetes mellitus. Among those with type 2 diabetes mellitus, 46% experienced a reduction in HbA1c to below diabetic cut offs. Compared to baseline, the Metabolic Syndrome Severity Score decreased by 30% among those with metabolic syndrome, 11% among those with prediabetes, 26% among those with type 2 diabetes mellitus, and 38% among those with uncontrolled type 2 diabetes mellitus. Cardiorespiratory fitness, measured by the calculated Metabolic Equivalent of Task maximum, increased by 30% in the metabolic syndrome cohort, 28% in the prediabetic cohort, 29% in the type 2 diabetes mellitus cohort, 29% in the uncontrolled type 2 diabetes mellitus cohort, and 32% in the cohort with obesity.

      Conclusion

      Modifying lifestyle factors that trigger hyperinsulinemia provided pleiotropic improvements to all measured surrogate markers of insulin resistance, mitigated the progressive nature of the insulin resistance and metabolic syndrome‒related chronic pathologies, reduced Metabolic Syndrome Severity Score, and improved cardiorespiratory fitness. These results suggest that earlier identification of the diagnostic criteria of metabolic syndrome and/or Metabolic Syndrome Severity Score and the prompt initiation of a comprehensive therapeutic lifestyle approach would significantly mitigate disease burden.

      Graphical Abstract

      Keywords

      INTRODUCTION

      Primary care deliverable and/or referable
      • Curry SJ
      • Grossman DC
      • Whitlock EP
      • Cantu A.
      Behavioral counseling research and evidence-based practice recommendations: U.S. Preventive Services Task Force perspectives.
      lifestyle interventions are guideline-recommended first-line treatments for chronic conditions
      • Mechanick JI
      • Garber AJ
      • Grunberger G
      • Handelsman Y
      • Garvey WT
      Dysglycemia-based chronic disease: an American Association of Clinical Endocrinologists position statement.
      ,
      • Arnett DK
      • Blumenthal RS
      • Albert MA
      • et al.
      2019 ACC/AHA guideline on primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice guidelines.
      and are designed to provide quaternary prevention while mitigating disease progression. Unfortunately, these recommendations are underutilized, eliminating their potential to provide either health or economic value.
      The prevalence of individuals entering and progressing through the 4 stages of the dysglycemia-based chronic disease model—consisting of insulin resistance (IR), prediabetes (PreD), type 2 diabetes mellitus (T2DM), and vascular complications
      • Mechanick JI
      • Garber AJ
      • Grunberger G
      • Handelsman Y
      • Garvey WT
      Dysglycemia-based chronic disease: an American Association of Clinical Endocrinologists position statement.
      ―is increasing with major economic ramifications. For example, each new diagnosis of T2DM carries with it an average annual economic cost 25 times greater per person than that of PreD (>$13,000 vs $500 U.S. dollar [USD]).
      • O'Connell JM
      • Manson SM
      Understanding the economic costs of diabetes and prediabetes and what we may learn about reducing the health and economic burden of these conditions.
      Although the pathophysiologic mechanisms of metabolic syndrome (MetS) and hyperglycemia are considered different, IR is the fundamental defect in both conditions
      • Reaven GM
      Syndrome X: a short history.
      and is significantly associated with T2DM and coronary heart disease (CHD).
      • Lakka HM
      • Laaksonen DE
      • Lakka TA
      • et al.
      The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men.
      • Standl E
      Hyperinsulinemia and atherosclerosis.
      • Reaven GM
      Pathophysiology of insulin resistance in human disease.
      IR, PreD, T2DM, and vascular complications, including CHD, are prime contributors to U.S. healthcare costs,
      Centers for Medicare & Medicaid Services
      NHE Summary including share of GDP, CY 1960–2019 (ZIP).
      disease burden, and impaired quality of life.
      Prior studies suggest that more than 75% of Americans hypersecrete insulin during oral glucose testing.
      • Crofts C
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      • Kraft J
      Identifying hyperinsulinaemia in the absences of impaired glucose tolerance: an examination of the Kraft database.
      ,
      • Crofts CA
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      • Zinn C
      • Schofield G
      Hyperinsulinemia: a unifying theory of chronic disease?.
      When hyperinsulinemia is persistently triggered, IR develops.
      • Shanik MH
      • Xu Y
      • Skrha J
      • Dankner R
      • Zick Y
      • Roth J
      Insulin resistance and hyperinsulinemia: is hyperinsulinemia the cart or the horse?.
      Most insulin-resistant individuals will compensate by secreting insulin in larger amounts. Compensatory hyperinsulinemia is initially sufficient to prevent frank decompensation of blood glucose control but nevertheless directly increases CHD risk.
      • Reaven GM
      Syndrome X: a short history.
      Environmental and lifestyle factors, including diets, which trigger this hyperinsulinemic response are by their nature insulinogenic.
      Currently, more than 85% of American adults are considered metabolically unhealthy because they present with at least one of the following diagnostic criteria for MetS: triglycerides (TGs) ≥150 mg/dL, blood pressure (BP) ≥120/80 mm Hg, fasting glucose >100 mg/dL or HbA1c >5.6%, female with waist circumference >88 cm, female high-density lipoprotein cholesterol (HDL-C) <50 mg/dL, male with waist circumference >102 cm, male with HDL-C <40 mg/dL, and/or taking related medication.
      • Araújo J
      • Cai J
      • Stevens J
      Prevalence of optimal metabolic health in American adults: national health and nutrition examination survey 2009-2016.
      These are each independent risk factors for CHD, whereas hyperglycemia increases the risk of developing T2DM.
      • Reaven GM
      Syndrome X: a short history.
      • Lakka HM
      • Laaksonen DE
      • Lakka TA
      • et al.
      The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men.
      • Standl E
      Hyperinsulinemia and atherosclerosis.
      ,
      • Reaven GM
      Banting lecture 1988. Role of insulin resistance in human disease.
      The presence of multiple independent risk factors of MetS results in the compounding of the risk of developing CHD, and it is the presence of these abnormalities as a cluster that is the most common metabolic abnormality in those with known CHD.
      • Reaven GM
      Syndrome X: a short history.
      ,
      • Reaven GM
      Pathophysiology of insulin resistance in human disease.
      ,
      • Reaven GM
      Banting lecture 1988. Role of insulin resistance in human disease.
      ,
      • Sachdeva A
      • Cannon CP
      • Deedwania PC
      • et al.
      Lipid Levels in patients hospitalized with coronary artery disease: an analysis of 136,905 hospitalizations in Get with the Guidelines.
      Each of the traditional diagnostic criteria of MetS correlates with a different manifestation of MetS according to sex and race/ethnicity.
      • Gurka MJ
      • Lilly CL
      • Oliver MN
      • DeBoer MD
      An examination of sex and racial/ethnic differences in the metabolic syndrome among adults: a confirmatory factor analysis and a resulting continuous severity score.
      Both aerobic exercise and resistance training improve fitness. When these modalities are combined, they have been shown to improve glycemic control.
      • Huang L
      • Fang Y
      • Tang L
      Comparisons of different exercise interventions on glycemic control and insulin resistance in prediabetes: a network meta-analysis.
      Cardiorespiratory fitness (CRF) is known to be an independent risk factor for morbidity and mortality,
      • Blair SN
      • Kohl HW
      • Paffenbarger RS
      • Clark DG
      • Cooper KH
      • Gibbons LW
      Physical fitness and all-cause mortality. A prospective study of healthy men and women.
      yet it is seldom (if ever) monitored and/or used as a clinical marker in primary care; therefore, improvement of CRF is seldom a clinical directive.
      These areas of concern are compounded by primary medical care's existing knowledge gaps of how IR or MetS-related conditions may be identified and effectively managed with nonpharmaceutical interventions.
      • Tseng E
      • Greer RC
      • O'Rourke P
      • et al.
      National survey of primary care physicians’ knowledge, practices, and perceptions of prediabetes.
      In this study, we define the methods used in a comprehensive, team-based lifestyle modification program personally tailored to specifically target and modify lifestyle components known to trigger the hypersecretion of insulin and affect insulin sensitivity, and determine to what extent, if any, using this approach could alter markers of IR and MetS-related disease progression, as well as alter CRF and Metabolic Syndrome Severity Score (MSSS) in a large free-living patient population.

      METHODS

      Study Sample

      We retrospectively examined the records of 813 participants of a novel lifestyle therapy program that began delivering treatment in January 2012. This therapeutic lifestyle program was delivered in a U.S.-based medical fitness center using routine clinical care referrals and was not run as a research project. As such, pretreatment and/or follow-up laboratory and biometric values were not readily available for all participants. Some participants completed the program without laboratory values, whereas a few participants dropped out. A total of 536 free-living participants aged ≥18 years joined the program between January 2012 and January 2021 and had both pretreatment and follow-up visits ≥30 days apart, meeting the inclusion criteria (Figure 1).
      Initial and latest examination dates varied widely for each participant depending on the initiation of their treatment and the latest examination. We limited our analysis to patients who had initial and latest examination values reported, and only initial and latest values were reported for simplicity of reporting. We also identified smaller cohorts from the 536 total participants who met known clinical and diagnostic cut offs for MetS, PreD, T2DM, uncontrolled T2DM (HbA1c≥8%), and obesity on their initial examination (Figure 2).
      Figure 2
      Figure 2Selection flow chart of cohorts for individuals meeting the diagnostic criteria of disease at baseline.
      MetS, metabolic syndrome; PreD, prediabetes; T2DM, type 2 diabetes mellitus.

      Program Description

      This therapy is defined as high-intensity, primary care referable by the U.S. Preventive Services Task Force
      • Curry SJ
      • Grossman DC
      • Whitlock EP
      • Cantu A.
      Behavioral counseling research and evidence-based practice recommendations: U.S. Preventive Services Task Force perspectives.
      because of its frequency and number of encounters as well as its delivery in a community-based setting. This therapy was delivered to patients by the medical fitness center staff, in coordination with their primary care physician. Patients were self-referred or referred by their primary care providers to the medical fitness center as part of routine clinical care to attempt to correct negative health trajectories, assumed to be driven by suboptimal lifestyle components.

      Measures

      We evaluated this therapy's ability to modify surrogate markers of IR, such as blood cholesterol ratios, and the traditional diagnostic criteria of MetS, including hyperglycemia, along with modification of MSSS and CRF. The average follow-up period for each participant was 450 days (15 months). Baseline characteristics of these 536 participants suggest a high probability of MetS and risk of MetS-related disease within this population (Table 1). Using confirmatory factor analysis of 1999–2010 National Health and Nutrition Examination Survey data, the MSSS z-score was created to assess the probability and severity of MetS and T2DM.
      Table 1Characteristics and Outcomes for Participants Meeting Inclusion Criteria—≥18 Years Having Baseline Data and at Least Partial Latest Follow-Up ≥30 Days (n=536, 59.9% Female)
      Participant characteristics and outcomesMean baseline (units)Mean latest (units)Relative change (%)Mean change, SD ± (units)p-value
      Age (years) (n=536)59.3 (±11.6)60.8 (±11.7)2.71.5 (±2.1)<0.001
      Weight (kgs) (n=536)101.1 (±27.6)95.4 (±24.9)–5.2–5.8 (±7.8)<0.001
      BMI (kg/m²) (n=506)35.2 (±8.1)33.2 (±7.4)–5.1–1.9 (±2.6)<0.001
      Waist circumference female (cm) (n=165)107.2 (±15.5)102.9 (±15.8)–2.2–4.8 (±24.1)0.007
      Waist circumference male (cm) (n=88)118.9 (±19.8)116.1 (±17.3)–1.8–1.3 (±27.4)0.337
      Blood pressure (systolic/diastolic) (mm/Hg) (n=512)126 (±14.2)121.7 (±13.4)–2.6–4.2 (±16.0)<0.001
      76.1 (±9.0)73.3 (±9.0)–2.9–2.8 (±9.6)<0.001
      (HDL-C) female (mg/dL) (n=155)56.0 (±15.2)56.6 (±15.0)8.80.7 (±22.0)0.366
      (HDL-C) male (mg/dL) (n=197)44.0 (±11.3)46.3 (±10.6)9.41.7 (±14.6)0.164
      Triglyceride to HDL-C ratio (n=463)3.4 (±3.5)2.5 (±1.9)–12.7–0.8 (±2.5)<0.001
      Total cholesterol to HDL-C ratio (n=463)3.9 (±1.3)3.5 (±1.1)–7.5–0.4 (±0.9)<0.001
      HbA1c (%) (n=396)6.1 (±1.1)5.9 (±0.9)–3.7–0.3 (±0.6)<0.001
      Calculated CRF (METmax) (n=444)6.7 (±2.6)7.5 (±2.6)21.60.8 (±1.3)<0.001
      MSSS z-score (n=40)1.08 (±0.86)0.58 (±0.94)–57.8–0.51 (±0.69)<0.001
      CRF, cardiorespiratory fitness; HDL-C, high-density lipoprotein cholesterol; METmax, MET of task maximum; MSSS, Metabolic Syndrome Severity Score.
      Patients provided informed written consent for the use of their deidentified personal health information for review in this investigation. All patients were also informed in writing that at any time they could opt out and remove consent for the use of their deidentified personal health information.
      Face-to-face therapies were delivered in a U.S.-based medical fitness center. A remote version of the intervention was delivered using Health Insurance Portability and Accountability Act–compliant digital technologies. All therapies were delivered by low-cost, university-educated nurses, nutritionists, health coaches, and exercise physiologists working as an integrated team with the patients’ primary care providers for the management of medications.
      During the initial 3-month phase, there were >23 nutrition and wellness coaching patient encounters as well as initial evaluations and monthly re-evaluation sessions scheduled. This was true for both the face-to-face and remote versions. Individual treatment plans (ITPs), which included patient identification, demographics, clinical biomarkers, latest assessment values, current exercise prescription, latest nutrition and health coaching notes, and latest available laboratory values, were created by staff on initiation and then monthly during this time. ITPs were reviewed by the director and shared with all the patients’ providers.
      Long-term, step-down programming involving less frequent encounters with staff was provided from the fourth month and beyond at regular quarterly intervals. The goal of this phase was to continue developing and/or maintaining participant self-efficacy while also providing accountability to the patient's self-selected goals. Staff created ITPs quarterly, which were reviewed by the director and shared with all the patient's providers.
      A general prescription methodology was used as a standard operating procedure to ensure that prescriptions were appropriate, safe, and personalized. Much like medical treatment, prescription creation began with prescreening evaluations and assessments. Before beginning any exercise or evaluations, participants were taught how to identify signs and symptoms of cardiovascular disease and were instructed to report any such signs to staff immediately or seek prompt medical attention. Sedentary participants or those with moderate or higher cardiovascular disease risks were instructed to limit exercise intensity to light exertion or 9–11 on the Borg 6–20-point scale of perceived exertion for the first 12 workouts. Participants were asked to complete these 12 sessions in a 30-day window. After completing 12 workouts without signs or symptoms at light exertion, participants were encouraged to increase the intensity to reach an exertion of moderate or up to 13 on the Borg scale of exertion. The frequency, intensity, time, type, volume, and progression formula was used for exercise programming. Participants were taught how to use cardiorespiratory equipment and how to determine intensity using the MET of task level. For exercise outside the facility, participants were taught how to estimate MET level. Volume of exercise was prescribed using a MET/hour/week formula on the basis of the patient's current American College of Sports Medicine MET of task maximum (METmax) classification for their age and sex. Volume (MET/hours/week) recommendations were as follows: very poor CRF<5 MET/hours/week, poor CRF=5–10 MET/hours/week, fair CRF=10–15 MET/hours/week, good CRF=15–20 MET/hours/week, excellent CRF=20–25 MET/hours/week, and superior CRF>25 MET/hours/week. Progression of volume increased as CRF classification improved.
      Resistance training and correctional exercise prescription were created considering the participant's current movement competency. Movement competency was determined by completing a movement screen
      • Cook G
      • Burton L
      • Hoogenboom BJ
      • Voight M
      Functional movement screening: the use of fundamental movements as an assessment of function – part 1.
      with in-person participants, whereas movement questionnaires were completed by remote participants. Participants at risk of injury because of movement dysfunction were instructed on which exercises and movements were to be avoided because of the potential of injury until their movement competency had improved. Participants were educated about the benefits that resistance training provides to improve their insulin sensitivity and noninsulin-dependent glucose uptake.
      • Cartee G
      • Wojtaszweski J
      Role of Akt substrate of 160kDa in insulin-stimulated and contraction-stimulated glucose transport.
      Participants were encouraged to increase the frequency of resistance training to up to 3, 60-minute, group exercise therapy classes each week and encouraged to perform cardiorespiratory exercises, such as walking, on most other days of the week. These group classes focused on multi-station functional resistance training with timed work-to-rest ratios of 60:30 seconds. These group classes were provided as one of the primary exercise modalities. Individual physical demands during each class were modified by instructors to suit each participant's tolerance and movement competency. Patients training remotely were provided personalized resistance exercise prescriptions and access to online group classes.
      The nutritional strategy was to reduce the insulinogenic stimuli of the participant's diet. This meant eating a habitual diet of real, whole foods with a major reduction in the consumption of processed and ultraprocessed foods; appropriate protein consumption (∼1.0–1.5 grams/kilograms of Reference Body Weight)
      • Richter M
      • Baerlocher K
      • Bauer JM
      • et al.
      Revised reference Values for Intake of Protein.
      ; and increases in consumption of healthier, naturally occurring fats, together with therapeutic carbohydrate reduction (TCR). A total of 4 different levels of TCR were used in nutrition coaching.
      • Cucuzzella M
      • Riley K
      • Isaacs D
      Adapting medication for type 2 diabetes to a low carbohydrate diet.
      The initial and subsequent levels of TCR were prescribed in consideration of the current health status, medication use, age, activity level, and CRF level of each participant. In general, lower levels of reduction were recommended for older, less fit, less active participants and those with advanced metabolic dysfunction, such as hyperglycemia. The decision on the TCR level was also determined in consultation with the patient. There was essentially no focus on calorie counting. Patients were asked to log or photograph their food intake using a Health Insurance Portability and Accountability Act–compliant application to allow for nutritional coaching regarding the most appropriate food choices and timing. All dietary plans were constructed with these tenants and customized to each participant's health, activity level, tastes, sensitivities, and cultural requirements. Nutrition coaching sessions took place every other week during the first 12 weeks and quarterly thereafter, immediately after each quarterly re-evaluation.
      Health coaching sessions took place weekly for the first 12 weeks and then quarterly immediately after each quarterly re-evaluation. Patients were asked to consider their progress or lack thereof during these sessions and were then encouraged to set new goals.
      Quantity and quality of sleep, healthy stress management mechanisms, as well as other possible insulinogenic components of the participant's lifestyle were addressed in health coaching sessions to improve insulin sensitivity.
      • Knutson KL
      • Spiegel K
      • Penev P
      • Van Cauter E
      The metabolic consequences of sleep deprivation.
      ,
      • Yan YX
      • Xiao HB
      • Wang SS
      • et al.
      Investigation of the relationship between chronic stress and insulin resistance in a Chinese population.
      Participants were encouraged to develop improved sleep hygiene, such as sleeping in their own bed and in a cool (∼65°F) dark room, getting to bed at a usual time, limiting screen time before bedtime, and other techniques known to improve quality of sleep. These items were addressed if sleep quality and/or quantity were suspected to be inadequate and/or possibly having a negative health impact. Exercise is a known stress reducer, but other mechanisms to improve stress‒rest balance or sympathetic–parasympathetic balance were suggested if the current mechanisms being used were suspected to be insufficient. Participants were coached to experiment with and find additional beneficial mechanisms other than exercise and high-quality sleep, such as meditation, yoga, breathing techniques, and prayer depending on their personal preference. Participants were guided to relaxation applications and devices that provided biofeedback to gauge their progress in this area.
      The treatment was primarily a private-pay therapy because of limited coverage for such therapies by insurers. Defining cost was difficult because in-person and remote programs differ as did individual patient needs. The in-person version was approximately $99±20 USD/month or $1,188±240 USD annually, whereas the remote version was approximately $59±20 USD/month or $708±240 USD annually.
      Initial evaluations of metabolic biomarkers (height, weight, BMI, waist circumference, CRF, and resting BP) were made and repeated every 30 days during the initial 3 months and quarterly thereafter. Height was determined using a wall-mounted stadiometer, weight was determined using a medical grade digital scale, and BMI was calculated using these 2 data points. Waist circumference was determined using a spring-loaded body tape measure, and resting BP was taken using the protocols defined by the Centers for Disease Control and Prevention. CRF was assessed using the Ebbeling single-stage ramp, or for those using heart rate‒limiting medication, the 6-minute Walk Test was used. Movement competency was assessed using movement questionnaires or movement screens
      • Cook G
      • Burton L
      • Hoogenboom BJ
      • Voight M
      Functional movement screening: the use of fundamental movements as an assessment of function – part 1.
      during prescreening. Pretreatment, ongoing, and latest laboratory values (HbA1c and blood lipid concentrations) collected from Clinical Laboratory Improvement Amendments‒accredited diagnostic testing centers were used. When recent (≤90 days) laboratory measurements were not found in the statewide health database, patient's providers were contacted, and they were then entered into the medical fitness center's electronic medical records.

      Statistical Analysis

      The paired sample t-test was used to determine whether the mean difference between the preintervention and post-intervention parameters (i.e., anthropometric measurements and biochemical investigations) is significantly different than zero. Analysis was completed using R programming language, Version 3.6.3. A p-value of <0.05 was considered significant.

      RESULTS

      The 536-participant free-living population showed improved surrogate markers of IR, diagnostic criteria of MetS, and hyperglycemia, showing a drastically improved cardiometabolic risk profile. BMI decreased by 5.1% (–1.9 kg/m²), whereas weight decreased by 5.2% (–5.8 kg). Waist circumference decreased in both male (n=88) and female (n=165) populations by –1.8% (–1.3 cm) and –2.2% (–4.8 cm), respectively. Both systolic and diastolic BP (n=512) decreased by –2.6% and –2.9% (–4.2 mm/Hg, –2.8 mm/Hg), respectively. HDL-C in both the male (n=197) and female (n=155) population increased by 9.4% (1.7 mg/dL) and 8.8% (0.7 mg/dL), respectively. Ratios of TG to HDL-C (n=462) and total cholesterol (TC) to HDL-C (n=463) also improved, decreasing by –12.7% (–0.8) and –7.5% (–0.4), respectively. HbA1c decreased by –3.7% (–0.3) (n=396), showing improved glycemic control. CRF, represented as METmax, increased by 21.6% (0.8 MET) in this population (n=444), whereas MSSS z-score decreased by –57.8% (–0.51) (n=40), showing a reduction in the probability and severity of MetS and/or T2DM (Table 1).
      Within the cohort of participants known to meet the diagnostic criteria of MetS (n=202), hypertension (≥130 or ≥85 mm Hg) (n=197) improved as systolic and diastolic BPs reduced by 4.6% (–7.2 mm/Hg) and 3.8% (–3.8 mm/Hg), respectively, whereas normalization of BP was achieved in >60% overall (72 of 121 systolic, 32 of 53 diastolic). Central adiposity (large waist circumference) (female >88 cm, male >102 cm) decreased by 6.3% (–7.6 cm) in females (n=118) and 6.2% (–8.1 cm) in males (n=83). Low HDL-C concentrations (female <50 mg/dL, male <40 mg/dL) increased by 8.2% (+3.0 mg/dL) in females (n=116) and 4.9% (+1.3 mg/dL) in males (n=80). Hypertriglyceridemia (≥150 mg/dL) (n=195) decreased by 23.4% (–57.1 mg/dL), and reversal of MetS (<3 of 5 criteria) was seen in 42% (74 of 178), indicating a substantial reversal of the MetS as documented at the latest examination. CRF improved in the MetS cohort by 29.9%, and the MSSS z-score also improved, decreasing the probability of severe MetS and/or T2DM by 29.5% (Table 2). In participants with mild hyperglycemia (n=131), prediabetic HbA1c (≥5.7%‒6.4%) at baseline, HbA1c normalized (<5.7%) in 35% (–0.2) (46 of 131) (Figure 3 and Table 3), with only 1.5% (2 of 131) of participants with PreD progressing to T2DM (2.0 of 100 patient-years). CRF improved by 27.9% in those with PreD, and in the subsection of this cohort, where fasting glucose was available (n=8), the MSSS z-score was reduced, decreasing the probability of MetS and/or T2DM severity by 10.8% (Table 3).
      Table 2Outcomes for Participants Meeting ≥3 of the Diagnostic Criteria of MetS Excluding Hyperglycemia (n=202)
      Diagnostic criteria of MetS, calculated CRF, and MSSSMean baseline (units)Mean latest (units)Relative change (%)Mean change, SD± (units)p-valueNormalization of previously abnormal criteria at latest ≥30-day follow-up (#, %)
      Blood (triglycerides) ≥150 mg/dL (n=195)185.6 (±123.6)128.5 (±64.2)–23.4–57.1 (±92.9)<0.00170/123 (57.0%)
      Female with blood (HDL-C) <50 mg/dL (n=116)47.8 (±10.6)50.8 (±12.2)8.23.0 (±10.5)0.00121/71 (29.6%)
      Male with blood (HDL-C) <40 mg/dL (n=80)39.1 (±9.6)40.4 (±9.6)4.91.3 (±5.7)0.06214/48 (29.2%)
      Female with waist circumference >88 cm (n=118)114.8 (±16.0)107.2 (±14.2)–6.3–7.6 (±7.9)<0.0016/116 (3.8%)
      Male with waist circumference >102 cm (n=83)128.8 (±18.3)120.7 (±18.0)–6.2–8.1 (±7.1)<0.0017/79 (8.9%)
      Blood pressure ≥130 or ≥85 mm/Hg (n=201)130.8 (±13.9)123.5 (±13.7)–4.6–7.2 (±18.2)<0.00173/121 (60.3%)
      78.3 (±9.0)74.5 (±8.1)–3.8–3.8 (±10.8)<0.00132/53 (60.4%)
      Those with MetS Dx and a number of diagnostic criteria (n=202)3.6 (±0.7)2.7 (±1.1)–25.0–0.9 (±1.1)74/178 (41.6%)
      Calculated CRF (METmax) (n=161)6.0 (±2.5)7.3 (±2.8)29.91.3 (±1.5)<0.001
      MSSS z-score (n=19)1.5 (±0.8)1.1 (±0.9)–29.5–0.4 (±0.7)0.008
      #, number; CRF, cardiorespiratory fitness; Dx, diagnosis; HDL-C, high-density lipoprotein cholesterol; METmax, MET of task maximum; MSSS, Metabolic Syndrome Severity Score.
      Figure 3
      Figure 3HbA1c changes in participants with PreD from baseline: Distribution data of HbA1c values, including median (center horizontal line), first and third interquartile (top and bottom of the box), and outliers (dots) in 131 patients with PreD from baseline (HbA1c≥5.7% but <6.5%) and latest follow-up. A total of 34.8% (46 of 131) achieved and maintained normal HbA1c (<5.7%), and only 1.5% (2 of 131) progressed to T2DM after 280.2 days of average follow-up.
      PreD, prediabetes; T2DM, type 2 diabetes mellitus.
      Table 3Glycemia, Calculated CRF, and MSSS in Those With Prediabetes—HbA1c (%) ≥5.7 % and <6.5 at Baseline
      CriteriaMean baseline (units)Mean latest (units)Relative change (%)Mean change, SD± (units)p-valueNormalization of previously abnormal criteria at latest ≥30-day follow-up (#, %)
      HbA1c (≥5.7 but <6.5%) (n=131)5.9 (±0.2)5.8 (±0.3)–2.5–0.2 (±0.3)<0.00146/131 (35.1%)
      Calculated CRF (METmax) (n=112)6.5 (±2.4)7.8 (±2.6)27.91.3 (±1.6)<0.001
      MSSS z-score (n=8)1.4 (±1.1)1.2 (±0.8)–10.8–0.2 (±0.3)0.053
      #, number; CRF, cardiorespiratory fitness; METmax, MET of task maximum; MSSS, Metabolic Syndrome Severity Score.
      In those with more severe hyperglycemia diagnosed as T2DM, HbA1c was reduced to below T2DM cut offs (<6.5%) in 45.7% (37 of 81) (Figure 4). Of interest, in 6% (5 of 81) of the participants, HbA1c was reversed to normal values (<5.7%) without the risk of overmedicalization. This cohort of participants with T2DM at baseline had improved CRF by 28.9%, whereas they had a decreasing probability of MetS and/or T2DM through the reduction of their MSSS by 26.1%, though this result was not statistically significant (Table 4).
      Figure 4
      Figure 4HbA1c changes in participants with T2DM from baseline: Distribution data of HbA1c values, including median (center horizontal line), first and third interquartile (top and bottom of the box), and outliers (dots) in 81 patients with T2DM with HbA1c≥6.5% at baseline and latest follow-up. A total of 6.2% (5 of 81) of participants with T2DM have achieved and are maintaining normal HbA1c<5.7%, and 39.5% (32 of 81) achieved and are maintaining prediabetic HbA1c>5.6% but <6.5% after 374 days of follow-up on average.
      T2DM, type 2 diabetes mellitus.
      Table 4Glycemia, Calculated CRF, and MSSS in Those With Type 2 Diabetes—HbA1c (%) ≥6.5 at Baseline
      CriteriaMean baseline (units)Mean latest (units)Relative change (%)Mean change, SD ± (units)p-valueStage reversal (#, %)
      HbA1c (≥6.5%) (n=81)7.7 (±1.3)6.7 (±1.0)–13.6–1.1 (±1.0)<0.00137/81 (45.7%)
      Calculated CRF (METmax) (n=68)5.9 (±2.4)7.0 (±2.6)28.91.1 (±1.3)<0.001
      MSSS z-score (n=8)1.3 (±0.7)1.0 (±1.2)–26.1–0.4 (±1.6)0.186
      #, number; CRF, cardiorespiratory fitness; METmax, MET of task maximum; MSSS, Metabolic Syndrome Severity Score.
      Within the cohort of those with uncontrolled T2DM (HbA1c≥8, n=29), HbA1c values drastically improved with a reduction of 20.3% (HbA1c= –1.8%); these changes contributed to a reduction in the MSSS by 37.9%, though this result was not statistically significant (Table 5).
      Table 5Glycemia and Calculated CRF in Those With Uncontrolled T2DM—HbA1c (%) >8% at Baseline
      CriteriaMean baseline (units)Mean latest (units)Relative change (%)Mean change, SD ± (units)p-valueStage reversal (#, %)
      HbA1c (>8%) (n=29)9.0 (±1.3)7.2 (±1.3)–20.3–1.8 (±1.2)<0.0019/29 (31.0%)
      Calculated CRF (METmax) (n=27)5.3 (±2.3)6.6 (±2.6)29.21.3 (±1.2)<0.001
      MSSS z-score (n=4)1.2 (±0.4)0.8 (±1.2)–37.9–0.4 (±1.1)0.279

      #, number; CRF, cardiorespiratory fitness; METmax, MET of task maximum; MSSS, Metabolic Syndrome Severity Score; T2DM, type 2 diabetes mellitus.
      In the obese cohort (n=371), a clinically relevant weight reduction
      • Jeppesen J
      • Facchini FS
      • Reaven GM
      Individuals with high total cholesterol/HDL cholesterol ratios are insulin resistant.
      of 6.7% of body weight (–7.4 kgs) was achieved and maintained for an average of 411 days. In a subgroup of participants with obesity followed for >540 days (n=89), a –7.5 kgs (–6.2%) weight loss has been sustained for an average of 1,524 days (4.2 years). The overall obese cohort (n=272) showed increased CRF through increment in calculated METmax by 31.5%, whereas the patients with obesity followed for >540 days (n=51) improved and maintained better CRF through increment in METmax by 48.4% (Table 6).
      Table 6Weight Loss, CRF, and MSSS in all Participants with Obesity (BMI ≥30 kg/m²) at Baseline (n=371), and Those Followed >540 Days (n=89)
      CriteriaMean baseline (units)Mean latest (units)Relative change (%)Mean Change, SD ± (units)p-valueMean days of follow-up
      Weight all obese (kgs) (n=371)111.3 (±24.7)103.9 (±20.4)–6.7–7.4 (+/-8.4)<0.001496.9
      Weight obese followed >540 days (kgs) (n=89)117.3 (±25.6)109.7 (±24.6)–6.2–7.5 (±11.2)<0.0011,563.2
      Calculated CRF (METmax) all obese (n=272)6.2 (±2.4)7.3 (±2.6)31.51.1 (±1.5)<0.001411.2
      Calculated CRF (METmax) obese followed >540 days (n=51)6.8 (±2.7)7.3 (±2.6)48.40.5 (±2.0)0.0351,523.5
      CRF, cardiorespiratory fitness; METmax, MET of task maximum; MSSS, Metabolic Syndrome Severity Score.
      In patients with MetS, PreD, T2DM, and uncontrolled T2DM, all measured surrogate markers of lipoprotein IR improved. In MetS participants (n=201), a 16.3% decrease in the TC/HDL-C ratio (–0.7) (n=196) and a 35.9% decrease in the TG/HDL-C ratio (–1.7) (n=195) were observed while also observing a 15.9% decrease in low-density lipoprotein cholesterol (LDL-C) concentrations (–16.8 mg/dL) (n=193) (Table 7). In the prediabetic cohort, there was a 24.5% reduction in the TG/HDL-C ratio (–0.8) (n=135), whereas the TC/HDL-C ratio decreased by 10.5% (–0.4) (n=135). LDL-C concentrations were also reduced by 11.4% (–12.4 mg/dL) (n=134) in this population (Table 8). In those with T2DM, the TG/HDL-C ratio improved by 35.3% (–1.7) (n=78), and the TC/HDL-C ratio also improved by 16.1% (–0.7) (n=77), whereas LDL-C concentrations decreased by 17.7% (–17.7 mg/dL) (Table 9). In those with uncontrolled T2DM HbA1c (≥8%) (n=26), the TG/HDL-C ratio improved by 29.8% (–1.3), as did the TC/HDL-C ratio, decreasing by 18.1% (–0.8), whereas LDL-C concentrations decreased by 26.1% (–28.7 mg/dL) (Table 10).
      Table 7Markers of Lipoprotein Insulin Resistance, CHD Risk, CRF, and MSSS Among Those With MetS at Baseline
      CriteriaMean baseline (units)Mean latest (units)Relative change (%)Mean change, SD ± (units)p-value
      Total blood cholesterol to HDL-C ratio (n=196)4.4 (±1.3)3.6 (±1.0)–16.3–0.7 (±1.1)<0.001
      Triglyceride to HDL-C ratio (n=195)4.7 (±4.7)3.0 (±2.0)–35.9–1.7 (±3.5)<0.001
      LDL-C (mg/dL) (n=193)108.0 (±39.0)91.2 (±33.0)–15.9–16.8 (±34.5)<0.001
      CHD, coronary heart disease; CRF, cardiorespiratory fitness; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MetS, metabolic syndrome; MSSS, Metabolic Syndrome Severity Score.
      Table 8Markers of Lipoprotein Insulin Resistance, CHD Risk, CRF, and MSSS Among Those With PreD Diagnosis (HbA1c≥5.7 but <6.5%)
      CriteriaMean baseline (units)Mean latest (units)Relative change (%)Mean change, SD ± (units)p-value
      Total blood cholesterol to HDL-C ratio (n=135)3.9 (±1.1)3.5 (±1.0)–10.5–0.4 (±0.9)<0.001
      Triglyceride to HDL-C ratio (n=135)3.2 (±2.3)2.4 (±1.5)–24.5–0.8 (±1.7)<0.001
      LDL-C (mg/dL) (n=134)109.5 (±36.8)97.1 (±37.4)–11.4–12.4 (±24.8)<0.001
      CHD, coronary heart disease; CRF, cardiorespiratory fitness; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MSSS, Metabolic Syndrome Severity Score; PreD, prediabetic.
      Table 9Markers of Lipoprotein Insulin Resistance, CHD Risk, CRF, and MSSS Among Those With T2DM Diagnosis (HbA1c≥6.5%) at Baseline
      CriteriaMean baseline (units)Mean latest (units)Relative change (%)Mean change, SD ± (units)p-value
      Total blood cholesterol to HDL-C ratio (n=78)4.1 (±1.3)3.4 (±0.9)–16.1–0.7 (±1.0)<0.001
      Triglyceride to HDL-C ratio (n=77)4.8 (±4.4)3.1 (±2.1)–35.3–1.7 (±3.2)<0.001
      LDL-C (mg/dL) (n=77)99.8 (±36.4)82.1 (±29.6)–17.7–17.7 (±31.7)<0.001
      CHD, coronary heart disease; CRF, cardiorespiratory fitness; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MSSS, Metabolic Syndrome Severity Score; T2DM, type 2 diabetes mellitus.
      Table 10Markers of Lipoprotein Insulin Resistance, CHD Risk, CRF, and MSSS Among Those With Uncontrolled T2DM Diagnosis (HbA1c >8%) at Baseline
      CriteriaMean baseline (units)Mean latest (units)Relative change (%)Mean change, SD ± (units)p-value
      Total blood cholesterol to HDL-C ratio (n=26)4.2 (±1.2)3.5 (±0.9)–18.1–0.8 (±1.4)<0.001
      Triglyceride to HDL-C ratio (n=26)4.3 (±1.9)3.0 (±1.1)–29.8–1.3 (±1.9)<0.001
      LDL-C (mg/dL) (n=26)110.0 (±47.4)81.3 (±28.6)–26.1–28.7 (±50.2)<0.001
      CHD, coronary heart disease; CRF, cardiorespiratory fitness; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MSSS, Metabolic Syndrome Severity Score; T2DM, type 2 diabetes mellitus.

      DISCUSSION

      The concomitant improvement in the traditional diagnostic criteria for the MetS, including hyperglycemia, as well as other surrogate markers of IR such as the TG/HDL-C ratio and MSSS, indicates that participants’ insulin resistant state had improved and that the therapeutic lifestyle treatment program addressed the fundamental defect of their metabolic dysfunction.
      • Reaven GM
      Syndrome X: a short history.
      The authors consider the most important finding of this study to be that in a large free-living population, this novel lifestyle treatment program provided immediate and long-lasting pleiotropic improvements in all measured surrogate markers of IR and diagnostic criteria of the MetS, including hyperglycemia.
      Many participants with MetS normalized abnormal biological markers, including 57% of those with abnormal TG concentrations (<150 mg dL). Amazingly, 29% of males with low HDL-C achieved normal blood HDL-C concentrations, 30% of females with low HDL-C achieved normal HDL-C concentrations, and >60% of those with hypertension normalized their abnormal BPs (Table 2).
      Reductions in TC and TG with an increase in HDL-C concentrations were also seen in all groups, including those with MetS, PreD, and T2DM. Reductions in the TC/HDL-C and TG/HDL-C ratio (Table 7, Table 8, Table 9, Table 10) strongly suggest reduced lipoprotein IR as well as improvements in risk factors associated with CHD.
      • Jeppesen J
      • Facchini FS
      • Reaven GM
      Individuals with high total cholesterol/HDL cholesterol ratios are insulin resistant.
      ,
      • Hajian-Tilaki K
      • Heidari B
      • Bakhtiari A
      Triglyceride to high-density lipoprotein cholesterol to high-density lipoprotein ratios are predictors of cardiovascular risk in Iranian adults: evidence from a population-based cross-sectional study.
      The most remarkable changes occurred in those with PreD and T2DM. Thus, 45.7% of participants with T2DM achieved lowered and maintained blood HbA1c values below T2DM cut offs (<6.5%), indicating that their T2DM had been placed into at least partial remission
      • Karter AJ
      • Nundy S
      • Parker MM
      • Moffet HH
      • Huang ES
      Incidence of remission in adults with type 2 diabetes: the diabetes & aging study.
      (Table 4 and Figure 4). Similarly, 35.1% of persons with PreD reduced their HbA1c values to the normal range (<5.7%), indicating remission of the prediabetic state (Table 3 and Figure 3). This remission was maintained for a mean follow-up of 374 days in those with T2DM and 280 days in those with PreD.
      Only 2 of 131 subjects with PreD progressed to T2DM (Figure 3). This created an incidence rate of T2DM in a prediabetic population that is substantially lower than the rates reported in published literature. This program's impact appears to be superior to those reported for either the placebo or the lifestyle intervention group in the National Diabetes Prevention Program (NDPP).
      Diabetes prevention program research group
      Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.
      To qualify for the NDPP, individuals with PreD need to be both prediabetic and overweight or obese.
      Diabetes prevention program research group
      Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.
      It is important to acknowledge that being of normal weight and prediabetic is not uncommon. These normal-weight individuals are also at risk of developing T2DM as well as CHD. The 2 stated primary goals of the NDDP are a 7% weight loss/maintenance and 150 minutes of weekly physical activity. The outcomes of the NDPP suggest that it can reduce the incidence rate of T2DM in a population with PreD by 54% when comparing the intervention group with the placebo group. When comparing the results of the approach being investigated, the incidence rate of T2DM in this population with PreD was 98% better than that of the same placebo group. The authors would offer that this significant difference may originate because of the NDPP mistargeting root cause, blaming obesity for pathology primarily driven by IR.
      • Hyde PN
      • Sapper TN
      • Crabtree CD
      • et al.
      Dietary carbohydrate restriction improves metabolic syndrome independent of weight loss.
      ,
      • Mardinoglu A
      • Wu H
      • Bjornson E
      • et al.
      An integrated understanding of the rapid metabolic benefits of a carbohydrate-restricted diet on hepatic steatosis in humans.

      Limitations

      This study's limitations include self-selection bias of participants because this was a therapeutic intensive lifestyle program provided as part of routine primary care referrals and not a research project. As such, follow-up laboratory values and biometrics were not readily available for many participants. This intensive, tailored, therapeutic lifestyle program did not measure patient engagement, so it is unclear whether the program's outcomes are due to better facilitation of health behavior change. However, a mandatory component of any successful model of change is a patient fully informed as to their current negative health trajectory and its highly probable, unpleasant endpoints.
      • Washburn PJ
      Health ballistics: multiple reference point informed probability theory.
       Informed patients, such as those who participated in this program, tend to develop higher states of readiness leading to improved engagement.
      • Washburn PJ
      Health ballistics: multiple reference point informed probability theory.
      • Prochaska JO
      • DiClemente CC
      Stages and processes of self-change of smoking: toward an integrative model of change.
      In addition, this program was not evaluated using RCT methodology (i.e. randomization, control group, and blinding). However, because it pertains to prevention, a more comprehensive approach may provide solutions to multifactorial problems that an RCT design may miss. Use of and changes in medication and compliance and changes in self-efficacy and engagement would improve the strength of this paper, but these data were not readily available for analysis. Further investigation into quantifying these components is warranted. Only preclinical and postclinical and laboratory values were provided, creating a selection bias. This evaluation format was used for no other reason than the simplicity of reporting because this program was ongoing and because participants began, participated, and ended engagement according to their individual needs and tastes.

      CONCLUSIONS

      Our investigation suggests that this team-based, personalized, patient-centered lifestyle intervention focusing on progressive exercise training to increase CRF and the reduction of excess carbohydrate consumption resulted in improvements in markers of IR and decreased the MetS severity score while controlling cardiometabolic and diabetic risk factors, suggesting that it has the potential to provide value to all stakeholders. This evaluation shows that using a low-cost multidisciplinary team to deliver ongoing patient education and support improved CRF reduced markers of IR and MetS and significantly slowed the progression of PreD to T2DM, suggesting that when used, it may provide a reduction in healthcare costs.
      The 2018 American Association of Clinical Endocrinologists/Association College of Endocrinology Position Statement states that “If health care were to recognize the benefit of the earlier initiation of lifestyle treatment, clearly many more patients could be provided care that is closer to optimal than the current standard of care.”
      • Mechanick JI
      • Garber AJ
      • Grunberger G
      • Handelsman Y
      • Garvey WT
      Dysglycemia-based chronic disease: an American Association of Clinical Endocrinologists position statement.
      This lifestyle approach, using a low-cost medical fitness staff to support lifestyle modification, helped slow the progression of those who had previously entered the dysglycemia-based chronic disease spectrum and in many cases showed that stage reversal is possible, including remission of the hyperglycemic state. Earlier identification of MetS, including the possible use of the MSSS calculator and referral to such an intervention, may reduce disease burdens associated with T2DM and CHD associated with IR.

      ACKNOWLEDGMENTS

      The authors would like to thank and acknowledge Dileepa Ediriweera, MBBS, MSc, PhD, for his statistical analysis of the data; John Cripps for his proofreading and support; and LeahAnne Humphrey, BS, for her assistance with initial planning and the management of references.
      PC, MK, and KB report that they are employees of Restore Medical Fitness. No other disclosures were reported.

      CRediT AUTHOR STATEMENT

      Peter Cummings: Conceptualization, Data curation, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing–original draft, Writing–review and editing. Timothy David Noakes: Writing–original draft, Writing–review and editing. David M. Nichols: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Validation, Visualization, Writing–original draft, Writing–review and editing. Kathleen Berchou: Conceptualization, Data curation, Investigation, Resources, Validation. Maria Kreher: Conceptualization, Data curation, Investigation, Methodology, Project administration, Resources, Supervision, Validation. Paul J. Washburn: Investigation, Supervision, Validation, Writing–original draft, Writing–review and editing.

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